Therapeutic compounds and intermediates therefor

ABSTRACT

Compounds of the formula   EXHIBIT CENTRAL NERVOUS SYSTEM STIMULATING PROPERTIES AND ACT AS MUSCLE RELAXANTS.

United States Patent Yale et al. Feb. 25, 1975 THERAPEUTIC COMPOUNDS ANDPrimary Examiner-Donald G. Daus INTERMEDIATES THEREFOR AssistantExaminer.lames H. Turnipseed Attorney, Agent, or Firm-Lawrence S.Levinson; [75] Inventors: Harry Louis Yale, New Brunswick,

N.J.; Ramesh B. Petigara, Lansadle, Merle Smith Burton Rodney P21. [73]Assignee: E. R. Squibb & Sons, Inc., [57] ABSTRACT Princeton NiCompounds of the formula [22] Filed: July 26, 1973 R 21 Appl. No;382,804 N (32) (mm k [52] U.S. Cl. ..260/256.4 F, 260/256.4 B, N N

260/256.4 C, 260/256.4 N, Int Cl 260/2563 exhibit central nervous systemstimulating properties 581 Field of Search 260/2564 F, 256.5 R and actas muscle relaxants 3 Claims, No Drawings THERAPEUTIC COMPOUNDS ANDINTERMEDIATES THEREFOR OBJECTS OF THE INVENTION It is an object of thepresent invention to provide new compounds having central nervous system(CNS) stimulating activity. Another object is to provide new compoundshaving muscle relaxant properties. A further object is to provideintermediates for the preparation of the final compounds of theinvention. Yet another object is to provide a method for the preparationof both the intermediate and the final compounds of the presentinvention. Still another object is to provide a method for theadministration of the final compounds of the invention. A still furtherobject is to provide pharmaceutical compositions containing as activeingredients the final compounds of the present invention. These andother objects of the present invention will be apparent from thefollowing description.

SUMMARY OF THE INVENTION The compounds of the present invention have thefollowing formula I (CH wherein m may be I or 2; when m is l, R occupieseither the 4 or 5- positions of the original 2- aminopyrimidine, butwhen R is halogen, it occupies only position-5', when m is 2, the twoR-substituents occupy the 4- and 5-positions of the original 2-aminopyrimidine, but only one of the two R- substituents can be halogenand it must occupy the 5- position;

R may be the same or different and may be hydrogen, halogen (F, Cl, orBr), alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substitutedphenyl wherein the substituent may be halogen (F, Cl, Br or I), alkyl offrom 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;

R may be hydrogen, halogen (F, Cl, Br or I), alkyl of from I to 4carbons, alkoxy of from 1 to 4 carbons, alkylthio of from I to 4carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein eachalkyl radical may have from 1 to 4 carbons, trifluoromethyl,mono-substituted phenyl or monosubstituted phenyloxy wherein thesubstituent may be halogen (F, Cl, Br or I), alkyl of from 1 to 4carbons, alkoxy of from 1 to 4 carbons or trifluoromethyl; n is 2 or 3.and pharmaceutically acceptable acid addition salts thereof.

The foregoing compounds possess central nervous system stimulatingproperties and act as muscle relaxants.

DETAILED DESCRIPTION The final compound I of the present invention maybe prepared by reacting a 2aminopyrimidine II with ano-bromophenalkylene bromide III. This reaction takes place in anysolvent or solvent mixture in which the reactants can be dissolved andwh ichhas a boiling point of at least about C. Typical solvents arearomatic hydrocarbons, ethers, aliphatic alcohols or arylsubstitutedaliphatic alcohols. Toluene and xylene are examples of suitable aromatichydrocarbons. Monomethyl ether of diethylene glycol, dimethyl ether ofdiethylene glycol (diglyme), monomethyl ether of ethylene glycol ordimethyl ether of ethylene glycol (glyme) are examples of suitableethers. n-Amyl alcohol is an example of a suitable aliphatic alcohol,while benzyl alcohol is an example of a suitable aryl-substitutedaliphatic alcohol. Heating compounds II and III in a solvent asdescribed above, or a mixture thereof, at temperatures from about 100 toabout l40C for a period of several hours, typically'from about 3 toabout 24 hours produces a pyrimidinium compound IV. The latter isconverted to an imino compound V by treating with a water misciblealcohol and an alkali metal alkoxide of up to 3 carbon atoms. Thereaction takes place at room temperature over a period of from about Ito about 4 hours. Compound V may be converted to the final compound I bytreating with a water miscible alcohol and an alkali metal alkoxide ofup to 3 carbons in the presence of copper at a temperature of from about60 to about for several days, typically from about 4 to about 10 days.Alternatively, IV may be converted directly to I by heating at atemperature of from about 60C to about 120C for about 4 to 10 days,typically from about 6 to about 8 days in the presence of potassiumcarbonate and copper in a solvent such as dimethylformamide,dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene.Preferably, however, IV may be converted directly to I by heating at atemperature of from about 60 to about 120C for about 4 to 10 days,typically from about 6 to about 8 days in the presence of an alkalimetal hydroxide, alkali metal carbonate, tris-alkali metal phosphate,alkali metal metaborate or alkali metal tetraborate in a solventcomprising a mixture of water and a water miscible alcohol in thepresence of copper. Specific examples of suitable compounds includeLiOH, NaOH, KOl-l, RbOl-I, CsOH, Na CO K CO Rb CO CS2CO3, Na PO K3PO4,Rb PO4, CS3PO4, Na2B O Na B O K B O and K B O The ratios of water andalcohol in the mixture of water and a water miscible alcohol are suchthat a homogeneous single phase system results.

When m is l, and when R occupies only the 5- position of II and Roccupies only the 5-position (para to the bromine atom) of III, only oneisomer, 1, is

formed. When m is l, and when R occupies only the 4- position of Ila,and R occupies only the 5-position of III, two isomers, Ia and lb areformed via the intermediates IVa or Va and Nb and Vb, respectively. Whenm is 2, and since the two Rs occupy only the 4-, 5- positions and Roccupies only the 5-position of III, two isomeric products, Ia and lbare formed. These isomers, in all instances, can be separated byconventional procedure, e.g., fractional recrystallization or columnchromatography.

The following reaction sequence is illustrated by the followingequations:

The intermediates of formula III wherein n is 2 may be prepared bytreating an o-bromobenzyl alcohol VI with PBr at temperatures of fromabout 0 to about 100C for a period of from about I to about 6 hours. Theresulting o-bromobenzyl bromide VII is then treated with sodium cyanidein the presence of water and a water miscible alcohol to yield anobromophenylacetonitrile VIII. Treatment of the latter with an alcoholin the presence of concentrated sulfuric acid yields the correspondingester IX. Treatment of the latter with lithium aluminum hydride yieldsan obromophenethanol. Treatment of the latter with PBr at temperatureswithin the range of from about 0 to about 100 for a period of from about1 to about 6 hours yields the corresponding o-bromophenethyl bromide XI.The foregoing reaction sequence is illustrated by the followingequations:

@CHZOH \CCICH2BI VII The intermediates of formula Ill wherein n is 3 maybe prepared by treating a compound of formula XI with sodium cyanide inthe presence of water and a water miscible alcohol to yield ano-bromophenylpropionitrile XII. Treatment of the latter with an alcoholin the presence of concentrated sulfuric acid yields the correspondingester XIII. Treatment of the latter with lithium aluminum hydride yieldsan obromophenpropanol. Treatment of the latter with PBr at temperatureswithin the range of from about 0 to about 100C for a period of fromabout I to about 6 hours yields the corresponding o-bromophenpropylbromide XV. The foregoing reaction sequence is illustrated by thefollowing equations CH CH Br N XII CH CH CN R @cn ca cn oa XIV' PBr

cn ca ca ar When R is alkylthio the compounds of formula XI or XV may beprepared by nitrating an o-bromobenzyl alcohol XVI at 0C using a mixtureof nitric and sulfuric acids. The resulting isomeric mixture of nitrated2- bromobenzyl alcohols is separated by conventional techniques. Eachseparated isomer XVII may then be reduced to the corresponding amineXVIII by means of zinc and hydrochloric acid. Treatment of the aminoderivative XVIII with nitrous acid and then with sodium alkylmercaptideyields the corresponding alkylthio-2- bromobe n zyl alcohol XIX.

' 2) AlkylSNa CH OH XIX Treatment of the compound of formula XIX withPBr as shown in the sequence proceeding from X to XI, and from XIV to XVyields the compound of formula XI or XV wherein R is alkylthio.

When R is trifluoromethyl, the intermediate of formula VII may beprepared by reacting a trifluoromethylphenyl magnesium bromide XX withmethyl iodide to obtain a trifluoromethyl toluene XXI. Treatment of thelatter with bromine in the presence of iron powder at C yields abromo-substituted trifluoromethyl toluene XXII. Treatment of the latterwith bromine in the presence of light and a peroxide catalyst yieldsthe'corresponding bromo-trifluoromethylbenzyl bromide XXIII.

F3C CH I CH Br XXIII Compounds of formula III wherein R' is phenyl,halogen-substituted phenyl, alkyl'substituted phenyl, al-

koxy-substituted phenyl, or trifluoromethyl-substituted phenyl may beprepared by treating an aminosubstituted o-bromobenzoic acid XXVIII withacetic anhydride and then with nitrous acid. The resulting N-acetamido-N-nitroso-o-bromobenzoic acid XXIX is then treated withbenzene or an R-substituted benzene wherein R is halogen, alkyl, alkoxyor trifluoromethyl according to the procedure of Haworth et al. supra.The aryl-substituted o-bromobenzoic acid is then treated with LiAlH orAlH according to known tcch- 65 about four divided doses for bothactivities.

niques to yield the corresponding aryl-substituted obromobenzyl alcoholXXXI. The reaction sequence is as follows:

1) (ca col Q 2) mm .R=ha1o, alkyl, R, alkoxy or CF XXXI The compounds ofthe present invention may be administered to mammalian species ascentral nervous system stimulants and as muscle rclaxants. In the rat,responses to the stimulant activity of the compounds of the presentinvention include increased activity and body tremors. The musclerelaxant properties manifest themselves by responses that includedecreased limb tone, decreased grip strength, and limb paralysis. Inboth the stimulant and muscle relaxant activities, the

onset of activity IS rapid, 1.e., within about 15 minutes;

the activity persists for about 2 hours or longer. In the rat the dosagerange varies from about 6.25 to about mg/kg for both activities, whilein humans the dosage range varies from about 40 to about 2000 mg. dailyin In addition to serving as intermediates for the preparation ofcompounds of formula I, the pyrimidinium compounds of formula IV arethemselves effective bactericides.

Microbial bioassays, as described in The Microbial World, by R. Y.Stanier, M. Doudoroff and E. A. Adelberg, Prentice-Hall, Inc., EnglewoodCliffs, N. .1. 3rd, Ed., p. 858, are employed to determine thebactericidal properties of the pyrimidinium compounds IV of thisinvention. The bacteria employed include Staphylococcus aureus, 1,Streptococcus pyrogenes, 2, Salmonella schottmuelleri, 3, Salmonellagallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6,Escherichia coli, 7, Pasturella multocida, 8, and Mycobacteriumtuberculosis, 9.

1n the procedure, a sterile agar plate is seeded with the test organism,and then a number of glass cylinders are placed on its surface, forminga series of little cups. A known dilution of the compounds of thisinvention is added to each cup and the entire plate is then incubateduntil significant bacterial growth has occurred. The compounds of thisinvention diffuse out of the cup into the surrounding agar and produce azone of inhibition. In this fashion it is possible to find the minimuminhibiting concentration (mic), of the compound that produces arecognizable zone of inhibition. The following summarizes the data.

The compounds of the present invention in the described dosages may beadministered orally; however, other routes such as intraperitoneally,subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enclosed in hard or soft gelatin capsules, orthey may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compounds of this invention may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage in the compositions and preparations may, ofcourse, be varied and may conveniently be between about 5% to about 75%or more of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about and 200 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of Wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

As to the pharmaceutically acceptable salts, those coming within thepurview of the invention include the pharmaceutically acceptableacid-addition salts. Acids useful for preparing these acid-additionsalts include, inter alia, inorganic acids, such as the hydrohalic acids(e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid,and phosphoric acid, and organic acids such as maleic, fumaric,tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicyclic,succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic,p-acetamidobenzoic, or methanesulfonic.

The following examples illustrate the following invention without,however, limiting the same thereto. All temperatures are expressed indegrees Centrigrade.

EXAMPLE 1 l l,12-Dihydropyrimido[2,l-b][1,3]benzodiazepine A.o-Bromobenzyl Bromide To 187.0 g of o-bromobenzyl alcohol at roomtemperature, with stirring, is added dropwise, 271.0 g of phosphorustribromide. After the addition is complete, stirring is continued forthree hours at room temperature. The mixture is then heated at 100 for 3hours and poured into 6 kg of crushed ice. The hydrolysis mixture isextracted with three 600 ml portions of ether, the ether extracts arewashed, dried, and concentrated to give o-bromobenzyl bromide, bp. aboutl30l32(l5mm). B. o-Bromophenylacetonitrile To a suspension of 220.0 g ofsodium cyanide in 2 65 ml of water and 380 ml of absolute ethanol, isadded, while stirring, a solution of 911.0 g of o-bromobenzyl bromide in911 ml of ethanol. The reaction proceeds exothermally, but is eventuallyheated under flux for about 0.5 hour, then cooled in an ice-bath, andfiltered. The solid is washed with ether, the filtrate is concentrated,the residue is suspended in 300 m1 of water and extracted with three 500ml portions of ether. The ether extracts are washed, dried, and thesolvent is removed. The residue is distilled to give 730 g of the namedproduct, bp 141l42 (12mm). C. Ethyl-o-bromophenylacetate To a cooledsolution of 730.0 g of obromophenylacetonitrile in 2.9 l of absoluteethanol is added, dropwise, while stirring, 740 ml of concentratedsulphuric acid. The addition requires about 2 hours.

The reaction mixture is heated under reflux for nine hours, poured intoice water, and extracted with 2.5 1 of ether. The ether extracts arewashed, dried, and concentrated. The residue is distilled to give 780.0g of ethyl o-bromophenylacetate, bp. about ll5-l17 (4mm), n 1,5434.

D. o-Bromophenethyl alcohol To a stirred suspension of 106.0 g oflithium aluminum hydride in 3.7 l of anhydrous ether, is added,dropwise, a solution of 780.0 g of ethyl obromophenylacetate in 3.1 l ofanhydrous ether. The reaction mixture is stirred for about 3 hours andthen heated under reflux for about 5 hours. The mixture is cooled, thentreated dropwise with 800 ml of water, and 1.5 l of aqueous hydrochloricacid. The ether solution is washed, dried, concentrated, and the residueis distilled to give 554.0 g of o-bromophenyl alcohol, bp. about 130-132(8mm), n,, 1,5760.

E. o-Bromophenethyl bromide To 550.0 g of o-bromphenethyl alcohol, whilestirring, is added, dropwise, 375.0 g of phosphorus tribromide. Afterstirring for three hours at room temperature, the reaction mixture isheated on a steam bath for 3 hours and then poured into 6 kg of crushedice. The mixture is extracted with three 600 and two 200 ml portions ofether. The ether extracts are washed, dried, concentrated, and theresidue is distilled to give 531.0 g of o-bromophenethyl bromide, bp.about 86-88 (0.9mm), n 1.5922.

F. 2-Amino-1-(o-brom0phenethyl)pyrimidinium Bromide To a solution of212.0 g of o-bromophenethyl bromide in 400 ml of dry xylene is added asolution of 121.0 g of 2-aminopyrimidine in 400 ml of dry xylene. Themixture is heated under reflux for about 3 hours, cooled, and the xylenesolution is decanted from the crystalline solid. The solid is trituratedwith 300 ml of 2-propanol. filtered, and dried to give 138.0 g of theproduct. The xylene solution is again heated under reflux for 16 hoursand by the same procedure, an additional 43.0 g ofproduct is recovered.The total of about 181.0 g of product is recrystallized from 2-propanolto give 170.0 g of the title compound, mp. about 23 l232.

G. 11,12-Dihydropyrimido[2,1-b][1,3]benzodiazepine To a solution of 9.0g of Z-amino-l-(o-bromophenethyl)pyridinium bromide in 55 ml ofdimethylformamide is added 10.3 g of micronized, anhydrous potassiumcarbonate and 0.5 g of copper bronze. The mixtureis heated at 100 forabout 7 days under nitrogen while stirring, and then is filtered whilehot. The filtrate is concentrated to dryness in vacuo to give about 8.6g of residue. This is extracted with two 125 m1 portions of boilingdiisopropyl ether. The diisopropyl ether solution is treated with Darco,filtered, and concentrated to about 40 ml to give on cooling, about 7.2g of 11,12- dihydropyrimido[2,1-b][1,3]benzodiazepine, mp about 4546.

EXAMPLE 2 12,13-Dihydro-2-methylthio-1lH-pyrimido[2,1-b][1,3]-bcnzodiazocine A. 2-Bromo-5-mcthylthiobenzyl BromideZ-Bromo-S-methylthiobenzyl alcohol is prepared by the following sequenceof reactions: 2-bromo-5- nitrobenzoic acid is reduced to 2-bromo-5-aminobenzoic acid by means of iron and hydrochloric acid in aqueousethanol. The 2-bromo-5-aminobenzoic acid is diazotized with sodiumnitrite in aqueous sulfuric acid, and the diazonium compound treatedwith sodium methylmercaptide to give 2-bromo-5- methylthiobenzoic acid.The 2-bromo-5- methylthiobenzoic acid is converted to its methyl esterby heating under reflux with methanol-concentrated sulfuric acid, themethylester is isolated by ether extraction from the esterificationmixture, recovered from the ether solution, distilled for purification,and reduced with lithium aluminum hydride to yield2-bromo-5-methylthiobenzyl alcohol. Treatment of the preceding compoundwith PBr as described in part A of example 1 gives2-bromo-5-methylthiobenzyl bromide. B.3-(2-Bromo-5-(methylthio)phenyl)-1-propanol To a suspension of 25.0 g ofmagnesium ribbon in a solution of 0.5 g of iodine in 550 ml of anhydrousether is added 5 ml of a solution of 296.0 g of2-bromo-5-(methylthio)benzyl bromide in 250 m1 of anhydrous ether. Thereaction is initiated by gentle heating, and the remainder of thesolution is then added dropwise so as to maintain a reflux.Subsequently, the mixture is heated and stirred under reflux for 1 hour,and then cooled to 10. A stream of nitrogen gas that has been bubbledthrough a reservoir containing 48.0 g of ethylene oxide is introducedinto the reaction mixture. The addition of the ethylene oxide requirestwo hours. The mixture is subsequently stirred as it warms to roomtemperature, is stirred for four hours at room temperature, and thenhydrolyzed by pouring on a mixture of 1 kg of ice and 55.0 g of ammoniumchloride. Extraction with ether, followed by conventional workup of theether solution, yield 210.0 g of 3-[(2-bromo-5-(methylthio)phenyl]-l-propanol, bp, about 125127 (0.6mm).C. 3-(2-Bromo-5-methylthiophenyl)propyl Bromide To 49.0 g of the productfrom (A), with stirring, is added, dropwise, 27.1 g of phosphorustribromide. The mixture is stirred subsequently for three hours at roomtemperature, then heated at -l00 for 3 hours, and then poured into 1 kgof crushed ice. Workup via ether extraction yields 52.7 g of3-(2-bromo-5-methylthiophenyl)propyl bromide, bp. about -102 (0.8mm). D.2-Amino-1-[3-(2-bromo-5-methylthiophenyl)- propyl]-pyrimidinium bromideTo a solution of 154.0 of 3-(2-bromo-4-methylthiophenyl)propyl bromidein 400 ml of dry xylene, is added a solution of 70.0 g ofZ-aminopyrimidine in 300 m1 of dry xylene and the mixture is heatedunder reflux for about 18 hours. The cooled xylene solution is decantedfrom the crystalline solid, the solid is triturated with 200 ml of2-propanol and filtered to give 117.0 g of crude product.Recrystallization of the latter from 2-propanol gives about 98.0 g of2-amino-l-[3-(2- bromo-4-methylthiophenyl)propyl]-pyrimidinium bromide.E. 12 ,l 3-Dihydro-2-methylthio-1 ll-l-pyrimido[2 ,1-b][1,3]-benzodiazocine To a solution of 8.1 g of2-amino-l-[3-(2-bromo-5- methylthiophenyl)propyl]-pyrimidinium bromidein 50 ml of dimethylformamide is added 10.3 g of micronized, anhydrouspotassium carbonate and 0.5 g of copper bronze. The mixture is heated at100 for about 3 hours under nitrogen whilc stirring, and then it isfiltered hot. The filtrate is concentrated to dryness in vacuo to giveabout 9.0 g of residue. This is extracted with two 120 ml portions ofboiling diisopropyl ether. The solution is treated with Darco, filtered,and concentrated to about 35 ml. This on cooling gives about 4.3 ofl2,l3-dihydro-2-methylthio-l1H- pyrimido[2,l-b][1,3]-benzodiazocine.

EXAMPLES 3-17 Following the procedure of example 1 (A) but substitutingan equivalent amount of the substituted 0- bromobenzyl alcohol in columnlfor o-bromobenzyl alcohol, there is obtained respectively, thecorresponding o-bromophenethyl bromide indicated in column 2. Reactionof the latter with Z-aminopyrimidine following the procedure of example1 (F) yields, respectively,

the pyrimidinium compound indicated in column 3. Treating the latterwith K CO and copper bronze following the procedure of example 1 (G)yields, respectively, the final product of column 4.

Example No. 1 2 3 4 ca C1 C1 ,cn --CH 9 ca CH 3. @CHZOH @CH CH BJ: 31 21g .81 fin 2 w I Br Br I 1 13: \I

4 c11 0 011 0 @/cH2..cH2 ocH e N/H2 CH2 ocrr cti t CHZCHZBI: @R .Br )gBr 1 Br H2 Br N on CH r CH CH 3 2 3 2 e cH -cr1 2 N cz1 -cr1 2 3 s. cnoa HZCHzB, @QLN .Br Q

Br H2 Br N E so ca cH so cu so 4,/CH2 cH2 2 3 CH s0 cH ca on c 9 2 2 HCH Br (3i Br NH 8 Br Br 2 N y y e I cn ou cn on o z z ar N crx ca 7. 0Br o O r O I O 0 s z a z CH ,ci-x -cn ca on N 2 2 2 3 CH20H ea er-1 B:C31 3 3 B: Br NH2 Br N F I F e cu CH2 F /CH2-CH2 F CH OK O 2 cH cH Br NBr Br NR2 Br N I g I L (CH (CH (CH ca U1 I 3 a 3 3 lo z z 2 2 T z z T zz so a 2 2 2 2 0 M /CH2CH2 s0 CHZOH cu ca m: (g1 r NH Br 9 r 2 .Br I NEXAMPLE 31 l l,l2-Dihydropyrimido[2,l b][1,3]benzodiazepine EXAMPLE 32A. l,Z-Dihydro-Z-iminol -(o-bromophenethyl )pyrimidine To a solution of3.3 g of sodium methoxide in 120 ml of anhydrous methanol is added 10.8g of 2-amin0-l- (o-bromophenethyl)pyrimidinium bromide, prepared asdescribed in example I (G). The solution is stirred under nitrogen for 2hours and then heated under reflux for hours. The solvent is removed invacuo and The ether solution is washed, dried, and concentrated in vacuoto give about 6.8 g of yellow solid. This is recrystallized from hexaneto give the name product, mp about 9798.

B. ll,l2-Dihydropyrimid0[2,l-b][1,3]benzodiazepine To a solution of 5.6g of l,Z-dihydro-Z-imino-l-(o- 'bromophenethyl)pyrimidine in 100 ml ofxylene is added 2.8 g of potassium carbonate and 0.5 g of copper bronzeand the mixture is heated under reflux for 3 hours, and filtered. Thefiltrate is concentrated in vacuo and the residue recrystallized fromdiisopropyl ether to give about 2.3 g of the title product, mp about45-46.

EXAMPLES 33-35 Following the procedure of example 1 (B) through 1 (G)but substituting the o-bromophenethylbromide in column I below for theo-bromobenzyl bromide in part B, and substituting for 2-aminopyrimidinein part F, the compound listed in column ll, there is obtained (frompart F), the pyrimidinium compound listed in column Ill and (from partG) the benzodiazocine compound the residue is treated with 200 ml ofanhydrous ether. listed in column IV.

Example No. I II c1 u e @ca cn sr Br N NH ca ca 8: N 2 ch 0 a: N

(CH CH NSO :CH CH B:: Oi

Br N *5 Example No. III IV 0 CH 33 F 3 3 3 c1 2 3. ca

' .Br J\ N a a: 2 I N M ex ea 3 2 7 (CH2) F CH CH N/( 2 3\ N NH B l 2 IOct-1 N N 061-1 6 (cu l u 2 un B.

EXAMPLES 36-39 Following the procedure of Example 1 but substituting for2-aminopyrimidine an equivalent amount of the Example No I N NH so u (cacu r j\2 s zx ulcn cu l a u z zyg .Br 0* Y N m B 2 CH Q (cu Y w N N11 Br3 H 0 (CH Y f N NH 5 NH Br s tit 71 ple 1 yields, respectively, thefinal compound indicated in column 3.

III

CH CH H C I iK CH H N [bl/l l (ca 21 )1 N 25 26 EXAMPLES 4()-5l tutingfor 2-aminopyrimidine in part F, the compound listed in column ll, thereis obtained (from part F) the Following the procedure of example 1 (B)through 1 pyrimidinium compound listed in column III and from (G) butsubstituting for o-bromobenzyl bromide in part part G the benzodiazepinecompound listed in column B, the compound listed in column I below, andsubsti- 5 IV.

Example No I II 1311 IV B 3 N Br 2 NR2 CH3 I CH3 H 0 (ca F HB %L;/(CHZ)3 IN/ 2 2 MR2 B N\N sen 3 1e Wg/(cazkdma W .Br 1 Br m N NH Br N\N BrCHca cs 1 v 2 2 3 6 fi B: l 2 I 2 .Br N

BrCH CH Br on on on cu CH CH CH 44. 2 :w 3 (S 3 2 a) 2 2 r 3 2 (CH r 8 W1 .Br k

NH N 2 B CH S O 47 Brcli cfi fi CH (CH CH (CH O CH: CH (CH )YNJCHQ Q o lo B! N1 a e u\ N N11 Br Example v V 1 II III IV BrCH CH 3 3 49.

. c1 @ii C1 q: Acs (HY (CH )2 o 1 Br 9 H2 Br .Br

BrCH ca 2 B: Q 50 j BR 2 /(ca2 2 o e 3 mi .ar

CF BrCH CH 2 Br 9 (CH B -2 it? e: at 2 N NH EXAMPLE 52 Preparation ofcapsule formulation Ingredient Milligrams per Capsule l l, lZ-Dihydropyrimido- [2,l-b1i1,3]benzodiazepine 400 Starch 8O Magnesiumstearate 5 The active ingredient, starch and magnesium stearate areblended together. The mixture is used to fill hard shell capsules of asuitable size at a fill weight of 485 The active ingredient, lactose andcorn starch (for mix) are blended together. The corn starch (for paste)is suspended in water at a ratio of 10 grams of corn starch per 80milliliters of water and heated with stirring to form a paste. Thispaste is then used to granulate the mixed powders. The wet granules arepassed through a No. 8 screen and dried at 120F. The dry granules arepassed through a No. 16 screen. The mixture is lubri' cated withmagnesium stearate and compressed into tablets in a suitable tabletingmachine. Each tablet contains 300 milligrams of active ingredient.

EXAMPLE 54 The sorbitol solution is added to 40 milliliters of distilledwater and the active ingredient is suspended therein. The sucaryl,saccharin, sodium benzoate, flavor and dye are added and dissolved inthe above solutioii. The volume is adjusted to milliliters withdistilled water,

Other ingredients may replace those listed for the above formulation.For example, a suspending agent such as bentonite magma, tragacanth,carboxymethylcellulose, or methylcellulose may be used. Phosphates,citrates 0r tartrates may be added as buffers. Preserva tives mayinclude the parabens, sorbic acid and the like and other flavors anddyes may be used in place of those listed above.

What is claimed is:

l. A compound of the formula wherein m is l or 2; when m is l, Roccupies either the 4- or 5-positions of the starting Z-aminopyrimidine,but when R is halogen it occupies only position-5; when m is 2, the twoR-substituents occupy the 4- and 5- positions of the starting2-aminopyrimidine, but only one of the two R-substituents can be halogenand it must occupy the 5-position.

R is the same or different and is hydrogen, F, Cl, Br, alkyl of from ito 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein thesubstituent is F, Cl, Br, I, alkyl of from l to 4 carbons, alkoxy offrom l to 4 carbons, or trifluoromethyl; provided that when R ishalogen, and m is l, R occupies only the 5-position in the startingZ-aminopyrimidine with the proviso that R may not be adjacent tertiaryalkyl;

R is hydrogen, F, Cl, Br, I, alkyl of from I to 4 car bons, alkoxy offrom I to 4 carbons, alkylthio of from I to 4 carbons, alkylsulfonylwherein the alkyl radical has from 1 to 4 carbons, phenyl, phenyloxy,sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical has from l to4 carbons, trifluoromethyl, mono-substituted phenyl or mono-substitutedphenyloxy wherein the substituent is F, Cl, Br, 1,

29 30 alkyl of from l to 4 carbons, alkoxy of from 1 to 4dihydropyrimidolil-bfli,3 ]ben;odia;ehihet carbons or trifluoromethyl; nis 2 or 3, 3. A compound of claim 1 having the name 12,13- andpharmaceutically acceptable acid addition salts dihydro-2-methylthio-llH-pyrimido[2,l-

thereof. b][ 1,3 lbenzodiazepine.

2. A compound of claim 1 having the name li ig UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION PATENT NO. 3 868 374 DATED 1 February25, 1975 INVENTOR(S) Harry Louis Yale et al.

It is certified that erro appears in The above-rdentified patent arrr}that said Letters Patenr are hereby corrected as shown below:

Column 2, line 67, "following" should read -foregoing. Column 10, line55, "flux" should read --reflux.

Signed and Scaled this twenty-second Day Of July 1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN Arresring Officer Commissioner of Patentsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 having the name11,12-dihydropyrimido(2,1-b)(1,3)benzodiazepine.
 3. A compound of claim1 having the name12,13-dihydro-2-methylthio-11H-pyrimido(2,1-b)(1,3)benzodiazepine.